Analysis of Epigenetic Age Acceleration and Healthy Longevity Among Older US Women
Authors: Purva Jain, Alexandra M. Binder, Brian Chen, Humberto Parada, Linda C. Gallo, John Alcaraz, Steve Horvath, Parveen Bhatti, Eric A. Whitsel, Kristina Jordahl, Andrea A. Baccarelli, Lifang Hou, James D. Stewart, Yun Li, Jamie N. Justice, Andrea Z. LaCroix
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Accelerated biological aging is associated with decreased physical capability and cognitive functioning, which are associated with increased risk of morbidity and mortality. <h3>Objective</h3> We investigated associations between epigenetic age acceleration (EAA), a biomarker associated with aging, and healthy longevity among older women. <h3>Design, Setting, and Participants</h3> This cohort study was a secondary analysis of participants in the Women's Health Initiative (WHI) who were eligible to survive to age 90 years by September 30, 2020. Participants were located in multiple centers. This study was restricted to women with genome-wide DNA methylation data, generated from baseline blood samples within 3 WHI ancillary studies. Median (IQR) follow-up times from baseline were 21.6 (19.6-22.9) years and 21.4 (19.8-22.7) years for women who survived to age 90 years with and without intact mobility, respectively, and 13.2 (8.8-16.7) for women who did not survive to age 90 years. Data were analyzed from December 2020 to July 2021. <h3>Exposures</h3> EAA was estimated using 4 established "clocks": Horvath pantissue, Hannum, Pheno, and Grim. <h3>Main Outcomes and Measures</h3> Using multinomial logistic regression, odds ratios (ORs) and 95% CIs were estimated for 3 healthy longevity outcomes for each clock: survival to age 90 years with intact mobility, survival to age 90 years without intact mobility, and no survival to age 90 years. <h3>Results</h3> Among 1813 women, there were 464 women (mean [SD] age at baseline, 71.6 [3.5] years) who survived to age 90 years with intact mobility and cognitive functioning, 420 women (mean [SD] age at baseline, 71.3 [3.2] years) who survived to age 90 years without intact mobility and cognitive functioning, and 929 women (mean [SD] age at baseline, 70.2 [3.4] years) who did not survive to age 90 years. Women who survived to age 90 years with intact mobility and cognitive function were healthier at baseline compared with women who survived without those outcomes or who did not survive to age 90 years (eg, 143 women [30.8%] vs 101 women [24.0%] and 202 women [21.7%] with 0 chronic conditions). The odds of surviving to age 90 years with intact mobility were lower for every 1 SD increase in EAA compared with those who did not survive to age 90 years as measured by AgeAccelHorvath (OR, 0.82; 95% CI, 0.69-0.96;<i>P</i> = .01), AgeAccelHannum (OR, 0.67; 95% CI, 0.56-0.80;<i>P</i> &lt; .001), AgeAccelPheno (OR, 0.60; 95% CI, 0.51-0.72;<i>P</i> &lt; .001), and AgeAccelGrim (OR, 0.68; 95% CI, 0.55-0.84;<i>P</i> &lt; .001). ORs were similar for women who survived to age 90 years with intact mobility and cognitive function (eg, AgeAccelHorvath: OR per 1 SD increase in EAA, 0.83; 95% CI, 0.71-0.98;<i>P</i> = .03) compared with women who did not survive to age 90 years. <h3>Conclusions and Relevance</h3> These findings suggest that EAA may be a valid biomarker associated with healthy longevity among older women and may be used for risk stratification and risk estimation of future functional and cognitive aging. Outcomes suggest that future studies may focus on the potential for public health interventions to counteract EAA and its association with poor health outcomes to lower disease burden while increasing longevity.